Pharmaceutical Formulations Containing Cannabidiol and Nicotine for Treating Smokeless Tobacco Addiction

ABSTRACT

In one aspect, a method of treating smokeless tobacco addiction comprising administering to an individual in need thereof a pharmaceutical composition comprising nicotine, a therapeutically effective amount of cannabidiol, and a pharmaceutically acceptable vehicle therefor. In some aspects, the composition is administered transmucosally, such as in an oral dosage form or nasal spray. In other aspects, the composition is administered transdermally. In another aspect, a chewable gum contains nicotine in at least a base portion and cannabidiol in at least an outer portion thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 15/426,617,filed Feb. 7, 2017, which claims priority under 35 U.S.C. § 119(e) toU.S. Application No. 62/336,990, filed May 16, 2016, the entiredisclosures of which are hereby incorporated by reference.

BACKGROUND

Nicotine has a number of psychoactive effects on the human body such asproducing an enhanced sense of well-being and relaxation and reducinganxiety and appetite. The intake of nicotine differs significantlybetween users of smokeless tobacco products and cigarette smokers. Forexample, the amount of nicotine absorption from a typical smokelesstobacco product can be four times or more than the amount absorbed fromsmoking a cigarette. Also, nicotine is absorbed more slowly from use ofsmokeless tobacco products, resulting in venous plasma levels thatplateau during and even after use of the product. While cigarettesmokers experience similar peak venous plasma levels as those ofsmokeless tobacco users, the venous plasma levels fall rapidly aftersmoking. See Benowitz, “Nicotine and Smokeless Tobacco,” CA-A CancerJournal for Clinicians, Vol. 38, No. 4, pp. 244-247 (1998).

Existing nicotine replacement therapy (NRT) products generally aredesigned to mimic nicotine levels achieved through cigarette smoking. Asa result, dosing of NRT products tends to be difficult for smokelesstobacco users. See American Cancer Society, “Guide to Quitting SmokelessTobacco,” (2014). Due to the different nicotine plasma profilesassociated with the use of smokeless tobacco products, as well as thefailure to address other (non-nicotine) factors contributing tosmokeless tobacco addiction including the anti-depressive effects oftobacco, existing NRT products to date have been largely unsuccessful inthe treatment of smokeless tobacco addiction.

SUMMARY

In one aspect, a method of treating smokeless tobacco addictioncomprises administering to an individual in need thereof apharmaceutical composition comprising nicotine and a therapeuticallyeffective amount of cannabidiol, and a pharmaceutically acceptablevehicle therefor. In some examples, the composition may be administeredto the individual by transmucosal delivery, such as via a chewing gum orother oral dosage form, or a nasal spray. In other examples, thecomposition may be administered to the individual by transdermaldelivery, such as via a transdermal patch.

In another aspect, an oral pharmaceutical dosage form comprises nicotineand a therapeutically effective amount of cannabidiol, and apharmaceutically acceptable vehicle therefor. In some examples, a dosageform includes a core that contains nicotine and an outer portion thatcontains cannabidiol. In some aspects, the oral dosage form may be achewable gum. In other aspects, the oral dosage form may be a tablet orcapsule.

In another aspect, a method of making a chewing gum product comprisesproviding a gum base containing nicotine. The gum base is coated withcannabidiol, and microwave radiation is applied to infuse thecannabidiol into at least an outer portion of the gum base.

The combination of cannabidiol and nicotine, especially when present incertain dosage forms as described herein, was found to provide asynergistic activity that is particularly efficacious for the treatmentof smokeless tobacco addiction. The combination thus presents a solutionto a long felt need, as existing NRT and other therapies for smokingcessation have been largely ineffective for treating smokeless tobaccoaddiction.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete understanding of the present invention and certainadvantages thereof may be acquired by referring to the followingdetailed description in consideration with the accompanying drawings, inwhich:

FIG. 1 is a graph showing monoamine oxidase-A (MAO-A) inhibitionactivity of cannabidiol.

FIG. 2 is a graph showing monoamine oxidase-B (MAO-B) inhibitionactivity of cannabidiol.

DETAILED DESCRIPTION

Aspects of the present specification disclose, in part, a pharmaceuticalcomposition. As used herein, the term “pharmaceutically acceptablecomposition” is synonymous with “pharmaceutical composition” and is onethat includes a therapeutically effective concentration of an activeingredient to produce an intended response. A pharmaceutical compositiondisclosed herein may be useful for medical or veterinary applications. Apharmaceutical composition may be administered to an individual alone,or in combination with other supplementary active ingredients, agents,drugs or hormones. In general, the compositions may be administered byany suitable route, including by not limited to orally, intravenously,transdermally, subcutaneously, topically, parenterally, or a combinationthereof. Non-limiting examples of suitable dosage forms that may be usedinclude chewing gum, lozenge, transdermal patch, and nasal spray.

A pharmaceutical composition may include a pharmaceutically acceptablecarrier that facilitates processing of an active ingredient intopharmaceutically acceptable compositions. As used herein, the term“pharmacologically acceptable carrier” is synonymous with“pharmacological carrier” and means any carrier that has substantiallyno long term or permanent detrimental effect when administered andencompasses terms such as “pharmacologically acceptable vehicle,”“stabilizer,” “diluent,” “additive,” “auxiliary” and “excipient.” Such acarrier generally is mixed with an active compound or permitted todilute or enclose the active compound and can be a solid, semi-solid, orliquid agent. It is understood that the active ingredients can besoluble or can be delivered as a suspension in the desired carrier ordiluent. Any of a variety of pharmaceutically acceptable carriers can beused including, without limitation, aqueous media such as, e.g., water,saline, glycine, hyaluronic acid and the like; solid carriers such as,e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin,talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like;solvents; dispersion media; coatings; antibacterial and antifungalagents; isotonic and absorption delaying agents; or any other inactiveingredient. Selection of a pharmacologically acceptable carrier candepend on the mode of administration. Except insofar as anypharmacologically acceptable carrier is incompatible with the activeingredient, its use in pharmaceutically acceptable compositions iscontemplated. Non-limiting examples of specific uses of suchpharmaceutical carriers can be found in Pharmaceutical Dosage Forms andDrug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams& Wilkins Publishers, 7th ed. 1999); REMINGTON: THE SCIENCE AND PRACTICEOF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins,20th ed. 2000); Goodman & Gilman's The Pharmacological Basis ofTherapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional,10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C.Rowe et al., APhA Publications, 4th edition 2003). These protocols areroutine procedures and any modifications are well within the scope ofone skilled in the art and from the teaching herein.

A pharmaceutical composition may include other pharmaceuticallyacceptable components (or pharmaceutical components), including, withoutlimitation, buffers, preservatives, tonicity adjusters, salts,antioxidants, osmolality adjusting agents, physiological substances,pharmacological substances, bulking agents, emulsifying agents, wettingagents, sweetening or flavoring agents, and the like. Various buffersand means for adjusting pH can be used to prepare a pharmaceuticalcomposition disclosed herein, provided that the resulting preparation ispharmaceutically acceptable. Such buffers include, without limitation,acetate buffers, citrate buffers, phosphate buffers, neutral bufferedsaline, phosphate buffered saline and borate buffers. It is understoodthat acids or bases can be used to adjust the pH of a composition asneeded. Pharmaceutically acceptable antioxidants include, withoutlimitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine,butylated hydroxyanisole and butylated hydroxytoluene. Usefulpreservatives include, without limitation, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuricnitrate, a stabilized oxy chloro composition and chelants, such as,e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide.Tonicity adjustors useful in a pharmaceutical composition include,without limitation, salts such as, e.g., sodium chloride, potassiumchloride, mannitol or glycerin and other pharmaceutically acceptabletonicity adjustor. The pharmaceutical composition may be provided as asalt and can be formed with many acids, including but not limited to,hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thanare the corresponding free base forms. It is understood that these andother substances known in the art of pharmacology can be included in apharmaceutical composition.

Cannabidiol and Nicotine

Cannabidiol (CBD),2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol,is one of at least 113 active cannabinoids identified in cannabis. It isa major phytocannabinoid, accounting for up to 40% of the plant'sextract. CBD may be prepared synthetically or extracted from appropriatenatural materials, such as cannabis, using well-known techniques. CBD isprone to decomposition in the acidic conditions present the stomach;therefore, in some aspects a suitable enteric coating or the like may beused to achieve a desired delivery of the active component.

2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzenediol

Unless otherwise clear from context, references herein to “cannabidiol”or “CBD” are inclusive of both naturally occurring andsynthetically-prepared compounds. The amount of CBD present in a dosageform may vary over a wide range, but by way of example often ranges fromabout 1 to about 300 mg, more usually from about 2 to about 250 mg, andtypically from about 3 to about 200 mg, about 4 to about 180 mg, about 5to about 160 mg, about 6 to about 140 mg, about 7 to about 120 mg, about8 to about 100 mg, about 10 to about 80 mg, about 12 to about 60 mg,about 15 to about 50 mg, or about 20 to about 45 mg.

Although the pharmacological properties of CBD have been studied to aconsiderable extent in recent years, its exact mechanism of action inthe human body is not fully understood. Linge et al., “Cannabidiolinduces rapid-acting antidepressant-like effects and enhances cortical5-HT/glutamate neurotransmission: role of 5-HT1A receptors,” J.Neuropharm 2015.12.017, observed that despite CBD exhibitingantidepressant effects, “its potential for treating major depression hasbeen poorly explored.” CBD elsewhere has been reported as being“ineffective” for inhibiting monoamine oxidase (MAO) activity. See“Safety, Side Effects of Cannabidiol,” Current Drug Safety, 2011, Vol.6, No. 4. Notwithstanding this prior report, the present inventor madethe surprising and unexpected discovery that CBD is effective forinhibiting MAO, including both MAO-A and MAO-B.

Nicotine may be prepared synthetically or extracted from appropriatenatural materials, such as tobacco, using well-known techniques.Nicotine may be present in the form of a nicotine salt, nicotine freebase, nicotine bound in a complex, or a suitable combination thereof.Non-limiting examples of nicotine salts include nicotine hydrochloride,nicotine dihydrochloride, nicotine monotartrate, nicotine bitartrate,nicotine sulfate, nicotine zinc chloride, nicotine salicylate, andcombinations thereof. Nicotine may be bound in a complex such as ionexchange resin, e.g., a weakly acidic cation exchange resin. An exampleof a weakly acidic cation exchange resin is polacrilex orpolymethacrilic acid (Amberlite IRP64 or Purolite C115HMR), as describedin U.S. Pat. No. 3,901,248, the disclosure of which is herebyincorporated by reference in its entirety. References to “nicotine”herein are inclusive of nicotine in any of the above-described forms.

The amount of nicotine present in a dosage form may vary over a widerange, but by way of example often ranges from about 0.1 to about 10 mg,more usually from about 0.5 to about 8 mg, and typically ranges fromabout 1 to about 6 mg, about 2 to about 5 mg, or about 3 to about 4 mg.

The ability of CBD to inhibit monoamine oxidase makes it particularlyeffective for treating smokeless tobacco addiction, especially when itis appropriately co-administered with nicotine to help alleviate the“reinforcing” addictive properties of tobacco. See Guillem et al.,“Monoamine Oxidase Inhibition Dramatically Increases the Motivation toSelf-Administer Nicotine in Rats,” J. Neurosci., 25(38):8593-8600(2005).

Chewing Gum

In some aspects, a pharmaceutical composition may be formulated as achewing gum. The formulation of gum bases can vary substantiallydepending on the particular product to be prepared and on the desiredmasticatory and other sensory characteristics of the final product. Byway of example, typical ranges of the gum base components include 5-80wt. % elastomeric compounds, 5-80 wt. % natural and/or synthetic resins(elastomer plasticizers), 0-40 wt. % waxes, 5-35 wt. % softener otherthan waxes, 0-50 wt. % filler, and 0-5 wt. % of other ingredients suchas antioxidants, colorants, and the like. The gum base may compriseabout 5-95 wt. % of the total weight of the chewing gum, often fromabout 10-60 wt. % or from about 40-50 wt. %.

Often a buffer is used. Examples of buffers that may be used includetris buffers, amino acid buffers, carbonate, including monocarbonate,bicarbonate or sesquicarbonate, glycerinate, phosphate,glycerophosphate, acetate, glyconate or citrate of an alkali metal, suchas potassium and sodium, e.g. trisodium and tripotassium citrate, orammonium, and mixtures thereof. Other examples of buffers include aceticacid, adipic acid, citric acid, fumaric acid, glucono-δ-lactone,gluconic acid, lactic acid, malic acid, maleic acid, tartaric acid,succinic acid, propionic acid, ascorbic acid, phosphoric acid, sodiumorthophosphate, potassium orthophosphate, calcium orthophosphate, sodiumdiphosphate, potassium diphosphate, calcium diphosphate, pentasodiumtriphosphate, pentapotassium triphosphate, sodium polyphosphate,potassium polyphosphate, carbonic acid, sodium carbonate, sodiumbicarbonate, potassium carbonate, calcium carbonate, magnesiumcarbonate, magnesium oxide, or any combination thereof

The buffer may to some extent be microencapsulated or otherwise coatedas granules with polymers and/or lipids being less soluble in salivathan is the one or more buffering agents. Such microencapsulationcontrols the dissolution rate whereby is extended the time frame of thebuffering effect. The amount of buffer may range from 0 to about 15% andoften ranges from about 0.5 to about 10% based on the total weight ofthe chewing gum.

Elastomers may be used to provide a rubbery, cohesive nature to the gum.Elastomers suitable for use in the gum base and gum may include naturalor synthetic types. Elastomer plasticizers may be used to vary thefirmness of the gum base. Their specificity on elastomer inter-molecularchain interaction (plasticizing) along with their varying softeningpoints cause varying degrees of finished gum firmness and compatibilitywhen used in base. This may provide more elastomeric chain exposure tothe alkane chains of the waxes.

The elastomers employed in the gum base may vary depending upon variousfactors such as the type of gum base desired, the texture of gumformulation desired and the other components used in the formulation tomake the final chewing gum product. The elastomer may be anywater-insoluble polymer known in the art, and includes those gumpolymers utilized for chewing gums and bubble gums. For example,polymers suitable for use in gum bases include, without limitation,natural substances (of vegetable origin) such as chicle gum, naturalrubber, crown gum, nispero, rosidinha, jelutong, perillo, niger gutta,tunu, balata, guttapercha, lechi capsi, sorva, gutta kay, and the like,and mixtures thereof. Examples of synthetic elastomers include, withoutlimitation, styrene-butadiene copolymers (SBR), polyisobutylene,isobutylene-isoprene copolymers, polyethylene, polyvinyl acetate and thelike, and mixtures thereof.

Natural resins may be used according to the invention and may be naturalrosin esters, often referred to as ester gums including as examplesglycerol esters of partially hydrogenated rosins, glycerol esters ofpolymerized rosins, glycerol esters of partially dimerized rosins,glycerol esters of tally oil rosins, pentaerythritol esters of partiallyhydrogenated rosins, methyl esters of rosins, partially hydrogenatedmethyl esters of rosins, pentaerythritol esters of rosins, syntheticresins such as terpene resins derived from alpha-pinene, beta-pinene,and/or d-limonene, and natural terpene resins.

Resins may be selected from terpene resins, such as those derived fromalpha-pinene, beta-pinene, and/or d-limonene, natural terpene resins,glycerol esters of gum rosins, tall oil rosins, wood rosins or otherderivatives thereof such as glycerol esters of partially hydrogenatedrosins, glycerol esters of polymerized rosins, glycerol esters ofpartially dimerized rosins, pentaerythritol esters of partiallyhydrogenated rosins, methyl esters of rosins, partially hydrogenatedmethyl esters of rosins or pentaerythritol esters of rosins andcombinations thereof.

Other chewing gum ingredients may be selected from bulk sweeteners,flavors, dry-binders, tableting aids, anti-caking agents, emulsifiers,antioxidants, enhancers, absorption enhancers, buffers, high intensitysweeteners, softeners, colors, and combinations thereof. Non-limitingexamples of emulsifiers include cyclodextrins, polyoxyethylene castoroil derivatives, polyoxyethylene alkyl ethers, macrogol alkyl ethers,block copolymers of ethylene and propylene oxides, polyoxyethylene alkylethers, polyoxyethylene glycols, polyoxyethylene sorbitan fatty acidesters, polyoxyethylene (20) sorbitan monostearates, polyoxyethylene(20) sorbitan monooleates, polyoxyethylene stearates, sobitan esters,diacetyl tartaric ester of monoglycerides, lactylated monoglycerides,and combinations thereof. The amount of emulsifiers often ranges fromabout 0.1% to about 25 wt. % based on the total weight of the chewinggum.

Petroleum waxes aid in the curing of the finished gum made from the gumbase as well as improve shelf life and texture. Wax crystal sizeinfluences the release of flavor. Those waxes high in iso-alkanes have asmaller crystal size than those waxes high in normal-alkanes, especiallythose with normal-alkanes of carbon numbers less than 30. The smallercrystal size allows slower release of flavor since there is morehindrance of the flavor's escape from this wax versus a wax havinglarger crystal sizes. The compatibility of gum bases made usingnormal-alkanic waxes is less when compared to gum bases made withiso-alkanic waxes.

Petroleum wax (refined paraffin and microcrystalline wax) and paraffinwax are composed of mainly straight-chained normal-alkanes and branchediso-alkanes. The ratio of normal-alkanes to iso-alkanes varies.

The normal-alkanic waxes typically have carbon chain lengths >C-18 butthe lengths are not predominantly longer than C-30. The branched andring structures are located near the end of the chain for those waxesthat are predominantly normal-alkanic. The viscosity of normal-alkanicwaxes is <10 mm²/s (at 100° C.) and the combined number averagemolecular weight is <600 g/mole.

The iso-alkanic waxes typically have carbon lengths that arepredominantly greater than C-30. The branched chains and ring structuresare located randomly along the carbon chain in those waxes that arepredominantly iso-alkanic. The viscosity of iso-alkanic waxes is greaterthan 10 mm²/s (at 100° C.) and the combined number average molecularweight is >600 g/mole. Synthetic waxes are produced by means that areatypical for petroleum wax production and are thus not consideredpetroleum wax. The synthetic waxes may include waxes containing branchedalkanes and copolymerized with monomers such as, but not limited topropylene, polyethylene, and Fischer Tropsch type waxes. Polyethylenewax is a synthetic wax containing alkane units of varying lengths havingattached thereto ethylene monomers.

Waxes and fats are conventionally used for the adjustment of the textureand for softening of the chewing gum base when preparing chewing gumbases. Any conventionally used and suitable type of natural andsynthetic wax and fat may be used, such as for instance rice bran wax,polyethylene wax, petroleum wax (refined paraffin and microcrystallinewax), sorbitan monostearate, tallow, propylene glycol, paraffin,beeswax, carnauba wax, candelilla wax, cocoa butter, degreased cocoapowder and any suitable oil or fat, such as completely or partiallyhydrogenated vegetable oils or completely or partially hydrogenatedanimal fats.

Antioxidants prolong shelf life and storage of gum base, finished gum ortheir respective components including fats and flavor oils. Antioxidantssuitable for use in gum base include butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), betacarotenes, tocopherols, acidulantssuch as Vitamin C, propyl gallate, other synthetic and natural types ormixtures thereof.

A chewing gum may include other conventional components such assweeteners, including bulk sweeteners, sugar sweeteners,sugar-substitute sweeteners, artificial sweeteners, high-intensitysweeteners, or a combination thereof. Bulk sweeteners may constitutefrom about 5 to about 95% by weight of the chewing gum, more typicallyabout 20 to about 80% by weight, about 30 to 70%, or about 30 to 60% byweight of the gum.

Useful sugar sweeteners are saccharide-containing components commonlyknown in the chewing gum art including, but not limited to, sucrose,dextrose, maltose, dextrins, trehalose, D-tagatose, dried invert sugar,fructose, levulose, galactose, corn syrup solids, and the like, alone orin combination.

Sorbitol can be used as a non-sugar sweetener. Other useful non-sugarsweeteners include, but are not limited to, other sugar alcohols such asmannitol, xylitol, hydrogenated starch hydrolysates, maltitol, isomalt,erythritol, lactitol and the like, alone or in combination.

High intensity artificial sweetening agents can also be used alone or incombination with the above sweeteners. Non-limiting examples of highintensity sweeteners include sucralose, aspartame, salts of acesulfame,alitame, saccharin and its salts, cyclamic acid and its salts,glycyrrhizin, dihydrochalcones, thaumatin, monellin, sterioside and thelike, alone or in combination. In order to provide longer lastingsweetness and flavor perception, it may be desirable to encapsulate orotherwise control the release of at least a portion of the artificialsweeteners. Techniques such as wet granulation, wax granulation, spraydrying, spray chilling, fluid bed coating, conservation, encapsulationin yeast cells and fiber extrusion may be used to achieve desiredrelease characteristics. Encapsulation of sweetening agents can also beprovided using another chewing gum component such as a resinouscompound.

Usage level of the artificial sweetener will vary considerably and willdepend on factors such as potency of the sweetener, rate of release,desired sweetness of the product, level and type of flavor used and costconsiderations. The active level of artificial sweetener may vary fromabout 0.001 to about 8% by weight, and often ranges from about 0.02 toabout 8% by weight. When carriers used for encapsulation are included,the usage level of the encapsulated sweetener will be proportionatelyhigher. Combinations of sugar and/or non-sugar sweeteners may be used ifdesired.

A chewing gum and/or gum base may include one or morefillers/texturizers, such as magnesium and calcium carbonate, sodiumsulfate, ground limestone, silicate compounds such as magnesium andaluminum silicate, kaolin and clay, aluminum oxide, silicium oxide,talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulosepolymers, such as wood, and combinations thereof.

A number of other well-known chewing gum components may be present,including but not limited to waxes, fats, softeners, fillers, flavors,anti-oxidants, emulsifiers, coloring agents, binding agents andacidulates. The chewing gum may be provided with an outer coating, suchas a hard coating, soft coating, edible film-coating, or any combinationthereof.

In some aspects, nicotine is compounded along with other components ofthe gum base such that nicotine is substantially uniformly contained inthe gum base. Nicotine or a nicotine complex may be provided on anadsorbent such as finely divided silicic acid, amorphous silica,magnesium silicate, calcium silicate, kaolin, clays, crystallinealuminosilicates, macaloid bentonite, activated carbon, alumina,hydroxylapatite, microcrystalline cellulose, or any combination thereof.Nicotine may be encapsulated to provide a desired controlled orsustained release thereof An example of a chewing gum that provides forsustained release of nicotine is described in U.S. 2007/0014887, thedisclosure of which is hereby incorporated by reference.

In some aspects, a gum base containing nicotine and the other componentsis first compounded, and then CBD is infused into an outer portion ofthe chewing gum. Alternatively, CBD may be compounded with nicotine andthe other components such that CBD and nicotine are each substantiallyuniformly contained in the gum base.

In one technique, CBD is applied to the exterior of a preformed gum baseand microwave radiation is applied under conditions sufficient to infusethe CBD into the outer portion of the gum base. The microwave radiationenergizes water molecules present in the gum base which allows thelarger CBD molecules to be absorbed through the surface and into anouter portion of the gum base. The resulting chewing gum may provide arapid release of CBD when first placed in the mouth and a sustainedrelease of nicotine, for example, as the individual begins to chew thegum.

A similar release profile may be achieved via an oral dosage form suchas a tablet, capsule, or the like. For example, a tablet may have a corelayer containing nicotine to provide a sustained release thereof, and anouter layer containing CBD to provide an immediate release thereof.Other combinations are possible. For example, one or both of the layersmay contain both CBD and nicotine so that the respective activecomponent(s) is released in both an immediate- and a sustained releasemanner.

Alternative Formulations

As an alternative to oral dosage forms such as chewing gums, CBD andnicotine may be provided in other delivery vehicles such as a nasalspray or transdermal patch for transmucosal or transdermal delivery ofthe active components, respectively. The details of such deliveryvehicles are well-known to persons skilled in the art and form no partof the present invention. For example, U.S. 2010/0236562, the disclosureof which is hereby incorporated by reference, discloses a pressurizedcontainer containing nicotine, oxygen, a propellant, and othercomponents which is designed to deliver nicotine by inhalation spray.U.S. Pat. No. 5,948,433, the disclosure of which is hereby incorporatedby reference, discloses an example of a transdermal patch having abacking layer, a liner layer, and a drug-containing adhesive layerdisposed between the backing layer and the liner layer.

As used herein, the term “treating,” refers to reducing or eliminatingin an individual a clinical symptom of smokeless tobacco addiction. Forexample, the term “treating” can mean reducing one or more symptoms ofsmokeless tobacco addiction by, e.g., at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, or more. Thesymptoms associated with smokeless tobacco addiction are well known andcan be determined by a person of ordinary skill in the art. Those ofskill in the art will know the appropriate symptoms or indicatorsassociated with smokeless tobacco addiction and will know how todetermine if an individual is a candidate for treatment as disclosedherein.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. The timing ofadministration can vary from individual to individual, depending uponsuch factors as the severity of an individual's symptoms. For example,an effective dose of a pharmaceutical composition disclosed herein canbe administered to an individual once or more daily for an indefiniteperiod of time, or until the individual no longer requires therapy. Aperson of ordinary skill in the art will recognize that the condition ofthe individual can be monitored throughout the course of treatment andthat the effective amount of a pharmaceutical composition disclosedherein that is administered can be adjusted accordingly.

A pharmaceutical composition disclosed herein may be administered to anindividual in combination with other therapeutic compounds to increasethe overall therapeutic effect of the treatment. The use of multiplecompounds to treat an indication can increase the beneficial effectswhile reducing the presence of side effects. In some examples, CBD andnicotine are co-administered without administering another monoamineoxidase inhibitor (MAOI).

Various modifications may be made without departing from the spirit orscope of the present invention. For example, although the pharmaceuticalcompositions disclosed herein are formulated for use in treatingsmokeless tobacco addiction, it should be recognized that thecompositions also may be effective for use in smoking cessation.

The following examples illustrate but do not limit the scope of thedisclosure set forth herein.

EXAMPLE 1

This example illustrates preparing a chewing gum containing nicotine andcannabidiol (CBD). Commercially available Nicorette® gum containing 4 mgnicotine per dose was used as a nicotine-containing gum base. Each pieceof gum was coated with 50 mg of CBD. Several of the coated gum pieceswere placed in a microwave oven. Microwave radiation was then applied atthe high setting for a brief period during which the CBD infused intothe outer surface of the gum pieces.

EXAMPLE 2

This example describes experiments for determining monoamine oxidase(MAO) inhibition activity for cannabidiol. MAOs are enzymes located onthe outer membrane of mitochondria and are involved in the catabolism ofmonoamine neurotransmitters. There are two well-characterizedisoenzymes: MAO-A, which predominantly catabolizes serotonin andnorepinephrine, and MAO-B, which preferentially catabolizes benzylamineand phenylethylamine. Dopamine and tyramine are metabolized by bothisoforms.

To detect the activity of MAO, a luminescent method (MAO-Glo Assay kit,from Promega, Cat # V1401) was used. In this method, a MAO substrate (aderivative of beetle luciferin provided in the kit) is mixed with thecompound to be tested (in this case, myosmine and control compounds).Then, the MAO-A or MAO-B enzyme is added to the mixture and incubatedwith the reaction for 1 hour at room temperature. The MAO enzymes, ifnot inhibited by the test compound, will convert the substrate intomethyl ester luciferin. Finally, a luciferin detection reagent (providedby the kit) is added (20 minutes at room temperature) to stop the MAOreaction and convert methyl ester luciferin into D-luciferin.D-luciferin reacts with luciferase to produce a luminescent signal,which is directly proportional to the D-luciferin concentration and thusthe MAO activity: the greater the amount of light produced the higherthe activity of MAO. The luminescent signal is measured and recordedusing a luminometer.

As shown in FIG. 1, cannabidiol was found to be a potent inhibitor ofMAO-A, in fact to an even greater extent than nornicotine (valuesappearing more leftward in FIG. 1 indicate a higher potency). At aconcentration of 7.5 mM (7,500 micromolar), CBD inhibited approximately50% of the MAO-A activity. The MAO-A inhibition activity for thepositive control, clorgyline, can be seen in the left-hand portion ofFIG. 1.

FIG. 2 shows that CBD also inhibits MAO-B activity, although to a lesserextent than MAO-A activity. At a concentration of 7.5 mM (7,500micromolar), CBD inhibited approximately 30% of the MAO-B activity. TheMAO-B inhibition activity for the positive control, deprenyl, can beseen in the left-hand portion of FIG. 2.

EXAMPLE 3

This example illustrates the treatment of an individual who was ahabitual user of smokeless tobacco products for more than 20 years. Theindividual previously had several unsuccessful attempts to quit his useof smokeless tobacco products, including nicotine replacement therapyand even hypnosis.

The individual began daily use of the chewing gum described in Example 1at periodic intervals during each day to satisfy cravings. Theindividual ceased the use of tobacco products immediately upon beginningtreatment. Following eight weeks of treatment, the individual still hadnot used tobacco products.

EXAMPLE 4

This example reports the results of a trial involving a group of tenindividuals who were habitual and chronic users of smokeless tobaccoproducts. Each of the ten individuals was given a supply of the chewinggum as described in Example 1 and instructed to use the gum as often asneeded over a period of 24 hours. At the conclusion of this period, allof the subjects (10/10) reported that they used the chewing gum in lieuof the smokeless tobacco products they normally would have consumed; andall of the subjects (10/10) reported that the chewing gum was effectiveto significantly block cravings for smokeless tobacco.

While particular embodiments have been described and illustrated, itshould be understood that the invention is not limited thereto sincemodifications may be made by persons skilled in the art. The presentapplication contemplates any and all modifications that fall within thespirit and scope of the underlying invention disclosed and claimedherein.

What is claimed is:
 1. An oral pharmaceutical dosage form comprisingnicotine, a therapeutically effective amount of cannabidiol, and apharmaceutically acceptable vehicle therefor.
 2. The oral pharmaceuticaldosage form of claim 1 which is a chewing gum.
 3. The oralpharmaceutical dosage form of claim 2 which contains nicotine in atleast a base portion and cannabidiol in at least an outer portionthereof.
 4. The oral pharmaceutical dosage form of claim 3 whichcontains from about 0.1 to about 10 mg of nicotine and from about 1 toabout 300 mg of cannabidiol.
 5. The oral pharmaceutical dosage form ofclaim 4 which contains from about 1 to about 5 mg of nicotine and fromabout 5 to about 200 mg of cannabidiol.
 6. The oral pharmaceuticaldosage form of claim 5 which contains from about 1 to about 4 mg ofnicotine and from about 6 to about 180 mg of cannabidiol.
 7. The oralpharmaceutical dosage form of claim 6 which contains from about 2 toabout 4 mg of nicotine and from about 7 to about 160 mg of cannabidiol.8. The oral pharmaceutical dosage form of claim 7 which contains fromabout 3 to about 4 mg of nicotine and from about 8 to about 140 mg ofcannabidiol.
 9. The oral pharmaceutical dosage form of claim 8 whichcontains from about 10 to about 100 mg of cannabidiol.
 10. The oralpharmaceutical dosage form of claim 9 which contains from about 15 toabout 50 mg of cannabidiol.
 11. The oral pharmaceutical dosage form ofclaim 1 which does not contain a monoamine oxidase inhibitor other thancannabidiol.
 12. A pharmaceutical dosage form comprising from about 1 toabout 4 mg of nicotine, from about 8 to about 100 mg of cannabidiol, anda pharmaceutically acceptable vehicle therefor.
 13. The pharmaceuticaldosage form of claim 12 which comprises an oral dosage form.
 14. Thepharmaceutical dosage form of claim 13 wherein the oral dosage comprisesa tablet or capsule.
 15. The pharmaceutical dosage form of claim 12which comprises a nasal spray.
 16. The pharmaceutical dosage form ofclaim 13, wherein the oral dosage form comprises a core layer containingnicotine and an outer layer containing cannabidiol.
 17. Thepharmaceutical dosage form of claim 16 which contains from about 2 toabout 4 mg of nicotine and from about 10 to about 80 mg of cannabidiol.18. The pharmaceutical dosage form of claim 17 which contains from about3 to about 4 mg of nicotine and from about 15 to about 50 mg ofcannabidiol.